Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4-(1H,3H)-dione (>2). Compound >2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC50 = 4.6 ± 2.0 μM), and cowpox virus (CV) (EC50 = 2.0 ± 0.3 μM). Compound >2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5′-monophosphorylation for antiorthopoxvirus activity. Compound >2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.
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